- Heart rate (HR)
Stroke volume (SV): The volume of blood pumped by the left or right ventricle in a single heartbeat.
- SV = end-diastolic volume (EDV) − end-systolic volume (ESV)
Pulse pressure: Difference between diastolic blood pressure (DP) and systolic blood pressure (SP) of the heart cycle (SP - DP).
- Normally: 30–40 mm Hg
- Directly proportional to SV and inversely proportional to arterial compliance
Ejection fraction (EF): The proportion of EDV ejected from the ventricle.
- EF = SV / EDV = (EDV - ESV) / EDV
- Normally = 50–70%
- Represents an index of myocardial contractility: e.g., ↓ myocardial contractility → ↓ EF (seen in systolic heart failure, where EF is < 40%)
Cardiac output: The volume of blood the heart pumps through the circulatory system per minute (∼ 5 L/min at rest)
- Cardiac output (CO) = heart rate (HR) × stroke volume (SV)
- Via Fick principle: cardiac output is proportional to the quotient of the total body oxygen consumption and the difference in oxygen content of arterial blood (before it enters the lungs) and mixed venous blood (after it leaves the lungs)
- Via mean arterial pressure (MAP): MAP = cardiac output (CO) × total peripheral resistance (TPR)
- As HR increases, diastole is shortened, which decreases CO due to less filling time.
Volumetric flow rate: The volume of blood that flows across a valve per second
- Volumetric flow rate (Q) = flow velocity (v) x cross-sectional area (A)
During exercise, the SV and HR initially both increase to maintain a constant CO. As the HR continues to increase, SV at some point remains equal and then even gradually decreases due to decreased filling time in the very fast-beating heart. A constant CO is then only maintained by an increasing HR. As HR continues to rise above 160 bpm, CO starts decreasing as SV falls faster than HR increases. A healthy young adult can increase his or her CO about 4–5 times the resting rate.
The cardiac cycle can be divided into two phases: the systole, in which blood is pumped from the heart, and the diastole, in which the heart fills with blood. Systole and diastole are each subdivided into two further phases, resulting in a total of four phases of heart action. Pressure and volume in the ventricles and atria change in a characteristic manner due to contraction and relaxation processes, with the pressure in the left ventricle changing the most and the pressure in the atria the least.
- Main function: ventricular contraction
- Occurs in early systole, directly after the atrioventricular valves (AV valves) close and before the semilunar valves open
- All valves are closed
- Ventricle contracts (i.e., pressure increases) with no corresponding ventricular volume change
- LV pressure: 8 mm Hg → ∼ 80 mm Hg (when aortic and pulmonary valves open passively)
- LV volume: remains ∼ 150 mL
- The period of highest O2 consumption
- Main function: Blood is pumped from the ventricles into the circulation and lungs.
- Follows isovolumetric contraction
- Occurs during systole, between the opening and closing of the aortic valve
- Ventricles contract (i.e., pressure increases) to eject blood, thereby decreasing the ventricular volume
- Pressure: first increases from ∼ 80 mm Hg to 120 mm Hg and then decreases until aortic and pulmonary valves close
- Volume: ejection of ∼ 90 mL SV (150 mL → 60 mL)
- Main function: ventricular relaxation
- Follows systolic ejection
- Occurs between aortic valve closing and mitral valve opening
- All valves closed (volume remains constant)
- The ventricle relaxes (i.e., pressure decreases) with no corresponding ventricular volume change until ventricular pressure is lower than atrial pressure and atrioventricular valves open
- Pressure: decreases to ∼ 10 mm Hg
- Volume: remains at ∼ 60 mm Hg
- Main function: ventricles fill with blood
- Follows isovolumetric relaxation
- Occurs in early diastole; immediately after mitral valve opening
- Blood flows passively from the left atrium to the left ventricle
- The largest volume of ventricular filling occurs during this phase
- Follows rapid filling
Occurs in late diastole; immediately before mitral valve closing
- Pressure: ∼ 8 mmHg
- Volume: ventricle fills with ∼ 90 mL (60 mL → 150 mL)
Left ventricular pressure-volume diagram
- Used to: measure cardiac performance
- Shape: roughly rectangular; each loop is formed in an anti-clockwise direction
- (1) End-diastolic state: left ventricle filled with blood
- (1) → (2): Isovolumetric contraction with closed mitral and aortic valves
- (2): Pressure becomes higher than the aortic pressure and the aortic valve opens → initiates ventricular ejection
- (2) → (3): Volume and pressure decrease until pressure falls below aortic pressure and aortic valve closes
- (3): End-systolic state
- (4): Pressure falls, volume remains constant (isovolumic relaxation)
- (4) → (1): Pressure falls below atrial pressure and mitral valve opens; the ventricle is filled with blood
- (1): End-diastolic point; contraction begins
The width of the volume-pressure loop is the SV (the difference between EDV and ESV).
- Pacemaker cells (e.g., sinus node) of the conduction system of the heart autonomously and spontaneously generate an action potential that spreads throughout the myocardium.
- The electrical excitation of the myocardium results in its contraction (electromechanical coupling).
- The phase of relaxation prevents immediate re-excitation (refractory period).
- See myocytes that initiate and coordinate contraction of the heart muscle : collection of nodes and specialized
- Normal course of electrical conduction: sinus node (pacemaker) creates an action potential → signal spreads across atria and causes their contraction: → signal reaches AV node and is slowed down → AV node conducts the signal to bundle of His down the interventricular septum to Purkinje fibers in myocardium → they spread the signal across the ventricles → the ventricles contract (electromechanical coupling)
The action potentials of the pacemaker centers are transmitted to the cells of the myocardium via the cardiac conduction system, thereby depolarizing the cells ( . As a result, voltage-activated calcium channels open, causing calcium ions to flow into the cardiomyocytes. Calcium binds to regulatory proteins of myofilaments (troponin) and allows interaction of actin and myosin. The muscle cell contracts. The exact course of the molecular interaction of actin and myosin ( ) is dealt with in the basics of .
Calcium channels and calcium pumps
Direction of flow
Activation phase (affected tissue)
|Voltage-gated (iCa)||Calcium channels on the surface of myocytes, which open at about -40 mV and allow intracellular calcium influx||Cell membrane|| |
Extracellular calcium → cytoplasm
|Plateau phase (myocardium) and raising phase (SV node)|
|Ryanodine receptor|| |
Calcium channel in the membrane of the sarcoplasmic reticulum that opens after binding of calcium (referred to as calcium-induced calcium release)
Membrane of SR
Ca2+ from SR → cytoplasm
|Plateau phase (myocardium)|
|Calcium pumps|| |
SERCA (sarcoplasmic Ca2+-ATPase)
Calcium pumps and exchanger that remove calcium from the cytosol, thereby terminating a contraction
Membrane of SR
Ca2+ in cytoplasm→ sarcoplasmic reticulum
Plateau phase (myocardium)
|Cell membrane||Ca2+ in cytoplasm → extracellular|
Other cation channels
All are located in the cell membrane.
|Name||Definition||Ion and direction of flow||Activation phase (affected tissue)|
|Funny channels (HCN, If)||Nonselective cation channels (e.g., for Na+, K+) in pacemaker cells that open as the membrane potential becomes more negative (hyperpolarized)||Cations extracellular → intracellular||Raising phase (sinus node)|
Fast sodium channels (INa)
Sodium channels that rapidly open and close following depolarization
Na+ extracellular → intracellular
|Inward rectifier K+ channels||Potassium channels that open below −70 mV and stabilize the resting potential of the myocardiocytes by outflow of potassium||K+ intracellular → extracellular||Resting potential (myocardium > sinus node)|
|Delayed rectifier K+ channels(IKr & IKs)|| |
Potassium channels that can be rapidly (IKr) or slowly (IKs) activated upon depolarization
|K+ intracellular → extracellular||Repolarization (sinus node and myocardium)|
The long plateau phase from slow Ca2+ channels allows the myocardium to contract and pump blood effectively.
|Myocardial action potential (myocardium, bundle of His, Purkinje fibers)||Pacemaker action potential (SA node and AV node)|
|Phase 0 (Upstroke and depolarization)|| |
|Phase 1 (Early repolarization)|| || |
|Phase 2 (Plateau phase)|| |
|Phase 3 (Repolarization)|| || |
| || |
Pacemaker cells have no stable resting membrane potential. Their special hyperpolarization-activated cation channels (funny channels) ensure a spontaneous new depolarization at the end of each repolarization and are responsible for automaticity of the heart conduction system! In sympathetic stimulation, more If channels open, increasing the heart rate.
Upstroke and depolarization of a pacemaker cell are caused by the opening of voltage-activated L-type calcium channels. In other muscle cells and neurons, upstroke and depolarization are caused by fast sodium channels!
To ensure the proper length of time for chamber emptying (during systole) and refilling (during diastole) before the next contraction, and to prevent tetany of cardiac muscle, it is imperative that every contraction of the myocardium is followed by a sufficiently long period of relaxation. Therefore, a heart muscle cell is not re-excitable for a short time after depolarization, which is known as the refractory period. Due to the very long action potential of cardiomyocytes (200–400 ms), the first excited cardiomyocytes are still refractory while the last are still excited. On the one hand, this prevents circulatory excitations and, on the other hand, gives the cardiomyocytes enough time to contract and relax, without being disturbed by re-excitation!
depolarization of a cardiomyocyte
the time from phase 0 until the next possible
- Ensures sufficient time for chamber emptying (during systole) and refilling (during diastole) before the next contraction
- Prevents tetany of cardiac muscle
- Depends on the number of sodium channels ready to be reactivated
- Absolute refractory period: The fast sodium channels are completely deactivated during the plateau phase of the action potential of the myocardium so that no new action potential can be generated.
- Effective refractory period: An interval of time during which stimuli cannot generate a new action potential in a depolarized cardiac cell. The sodium channels are in an inactivated state until the cell fully repolarizes.
- Relative refractory period: The fast sodium channels can be partly activated at a TMB -40 mV; a very strong stimulus can generate a new weak action potential in this state.
- Supernormal period: period of supernormal excitability of the myocardium during repolarisation (some parts of the heart are excited and others unexcited)
The firing frequency of the SA node is faster than that of other pacemaker sites (e.g., the AV node. The SA node activates these sites before they can activate themselves (known as overdrive suppression).
The plateau phase of the myocardial action potential is longer than the actual contraction. This allows the heart muscle to relax after each contraction and prevents a permanent contraction (so-called tetany)!
Cells in the relative refractory and supernormal period are particularly susceptible to arrhythmias (e.g., ventricular fibrillation) when exposed to an inappropriately timed stimulus. During cardioversion, shock delivery needs to be synchronized with an R wave on ECG (indicating depolarization) and needs to be avoided during the relative and supernormal refractory periods (T waves, indicating repolarization)!
The heart can generate excitement on its own due to its pacemaker cells, but it must adapt its work to daily life requirements. Adaptation to short-term changes is provided by the Frank-Starling mechanism. Long-term changes in cardiac activity are regulated by the autonomic nervous system. The electrical activity of the heart can be recorded by . See for an overview and interpretation of ECGs.
- Definition: Compensatory mechanism of the heart that adjusts stroke volume according to the venous return in order to maintain cardiac output.
- Aim: Stroke volume of both ventricles should remain the same
- Preload: The extent to which heart muscle fibers are stretched before the onset of systole. Depends on end-diastolic ventricular volume (EDV), which changes according to:
Afterload: The force against which the ventricle contracts to eject blood during systole.
- Afterload is primarily determined by the mean arterial pressure (MAP) in the aorta, which is influenced by total peripheral resistance.
- ↑ Afterload → ↑ left ventricular pressure → ↑ left ventricular wall stress
According to LaPlace's law, ↑ left ventricular pressure → ↑ left ventricular wall stress
- Left ventricular (LV) wall stress = (LV pressure × radius)/ 2×LV wall thickness
Autonomic innervation of the heart
The autonomic nervous system is able to regulate the heart action in the long term. Sympathetic fibers innervate both the atria and ventricles. Parasympathetic fibers only innervate the atria. The sympathetic nerve can therefore even alter the contraction force of the chambers (inotropy).
- Definition: Modulation of cardiac action by sympathetic and/or parasympathetic nerve fibers
- Aim: Long-term regulation of heart action
- Chronotropy: Any influence on the heart rate.
- Dromotropy: Any influence on the conductivity of cardiac tissue.
- Inotropy: Any influence on the force of cardiac muscle contraction.
- Lusitropy: Any influence on the rate of relaxation of cardiac muscle.
- Bathmotropy: Any influence on excitabilit of the heart muscle.
Sympathetic stimulation of the heart
- Area of innervation: atria and ventricles with fibers from the sympathetic cervical trunk
- Nerves: superior, middle, and inferior cardiac nerve
- Effect: increases heart rate, conduction, contractility, and relaxation
Mechanism of action
Activation of beta1 adrenergic receptors (Gs-protein coupled) of the heart by epinephrine and norepinephrine → ↑ activity of adenylyl cyclase → ↑ intracellular cAMP concentration in SA node cardiomyocytes, which then:
- Increases the conductance of funny sodium channels → ↑ influx of cations during spontaneous depolarization → faster attainment of the threshold potential for initiating the rhythmic cardiac action potential → ↑ heart rate (positive chronotropic)
- Activates protein kinase A (PKA), which leads to two effects:
- Phosphorylation of L-type Ca2+ channels in AV node → increased Ca2+ entry → increased Ca2+-induced Ca2+ release during action potential → increased contraction and conduction (positive dromotropic and inotropic)
- Phosphorylation of phospholamban → activation of sarcoplasmic reticulum Ca2+-ATPase (SERCA) → increased transport of Ca2+ back into sarcoplasmic reticulum after a contraction → faster relaxation (positive lusitropic)
- Activation of beta1 adrenergic receptors (Gs-protein coupled) of the heart by epinephrine and norepinephrine → ↑ activity of adenylyl cyclase → ↑ intracellular cAMP concentration in SA node cardiomyocytes, which then:
Parasympathetic stimulation of the heart
- Area of innervation: only the atria with fibers of the vagus nerve
- Cervical cardiac branches
- Thoracic cardiac branches
- Effect: reduces heart rate and atrial contractility
Mechanism of action: exerts its action on the heart through parasympathetic muscarinic ACh receptors (subtype M2)on SA and AV node cardiomyocytes
Activation of M2 receptors on SA node (negative chronotropic)
- Reduces the conductance of funny sodium channels via adenylyl cyclase and thus ↓ cAMP → ↓ pacemaker current (lengthens the rate of depolarization in the slow depolarization phase)
- Increases conductance of the slow potassium channels → hyperpolarization of the resting membrane potential (harder to overcome)
- Vagal fibers innervate the AV node (negative dromotropic): slows cardiac action potential propagation (can result in complete AV block)
- Activation of M2 receptors on SA node (negative chronotropic)
Initially, a diminished ejection fraction can be compensated by increased sympathetic tone, RAAS activation, ADH release, and the Frank-Starling mechanism. In the long term, however, these mechanisms increase cardiac work and lead to heart failure, which is why they are targeted by many drugs.
|Factors that increase SV||Factors that decrease SV|
|Preload|| || |
|Myocardial contractility|| || |
Myocardial oxygen demand increases with an increase in the HR, myocardial contractility, afterload, and diameter of the ventricle.
Heart sounds are sounds that are generated during physiological heart action. Additional heart sounds may be heard in the context of pathological processes (e.g., stenosis of heart valves). These pathological heart sounds are referred to as heart murmurs. Both heart sounds and heart murmurs can be heard using a stethoscope at characteristic points on the chest. For more information, please see , , , and in the learning card on .
To regulate organ perfusion, it is necessary to adapt circulatory parameters, such as pressure, volume status, and pH, with sensors and then process this information in a central regulatory center. The regulation center (in the medulla oblongata) acts on various effectors to control the blood flow in the short and long term.
Baroreceptors: stretch-sensitive nerve endings that detect blood pressure changes in systemic circulation and regulate it via signaling to the autonomic nervous system
- Location: in the aorta and wall of the carotid sinus on each side of the neck (high-pressure system)
- Component of hypertension, bradycardia, and respiratory depression) (
- Only suitable for making short-term changes in blood pressure because their activity (i.e., their firing frequency) adapts to a new blood pressure level within a few days.
Volume receptors: detect volume changes in pulmonary circulation and regulate the volume through the autonomic nervous system, atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH)
- Location: atria, pulmonary artery, and cardiac atria (low-pressure system)
- Increased volume (stretches atria)
- Decreased volume (stretches atria less)
- Diuresis reflex (= Gauer-Henry reflex): adapts ADH release in the hypothalamus according to blood pressure
Chemoreceptors: detect changes in pH and respiratory gases and regulate pH level, O2, and CO2 concentrations through respiration
- Mechanisms of action
If the baroreceptors of the carotid sinus are too sensitive, even small stimuli such as turning the head or the pressure of a shirt collar can lead to excessive blood pressure reduction and even fainting. This is referred to as carotid sinus syndrome.
Central regulation of peripheral blood flow
- Localization: vasomotor center (solitary nucleus) in medulla
- Receives information (afferents) via:
- Sends information (efferents) via:
- Arteries: can change BP by increasing or decreasing resistance
- Veins: can change circulating blood volume by adapting venous tone
- Heart: can influence blood pressure by changing stroke volume and heart rate
|Sympathetic stimulation||Parasympathetic stimulation|
|Arteries||Arterial constriction → ↑||Arterial vasodilation by means of releasing NO only in coronary arteries and vessels of the penis (erection)|
|Veins||Venous constriction → ↑ preload→ ↑ stroke volume||Venous dilatation → ↓ preload → ↓ stroke volume|
|Heart||↑ Contractility, ↑ heart rate||↓ Heart rate|
- Increased BP → ↑ firing frequency of baroreceptors (triggers baroreceptor reflex in brain stem) → ↑ parasympathetic stimulation and ↓ sympathetic innervation → vasodilatation → HR, SV, and BP decrease.
Kidneys: can influence blood volume by increasing or decreasing diuresis
- Renin-Angiotensin-Aldosterone-System (RAAS) is stimulated by:
- Mechanism of action: release of renin from the juxtaglomerular cells → activation of RAAS → direct vasoconstriction and ↑ extracellular volume (↑ sodium and water reabsorption, ↓ K+, ↑ pH)
- Atrial reflex (via ANP) and diuresis reflex (via ADH)
The renin-angiotensin-aldosterone system plays a key role in long-term blood pressure regulation and therefore is an ideal target when it comes to lowering a patient's blood pressure. While beta blockers decrease renin release by the kidneys, the conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme (ACE) can be influenced by so-called ACE inhibitors (e.g., ramipril, enalapril). The effect of angiotensin II on receptors of target cells can be inhibited by AT1 receptor antagonists (e.g., candesartan, losartan).
In case of inadequate perfusion of organs and disturbed microcirculation (e.g., hypovolemic shock, cardiogenic shock, distributive shock), hypoperfusion is registered by baroreceptors and volume receptors, which leads to an increase in sympathetic tone. To maintain adequate brain and heart perfusion, the blood supply to the extremities (muscle, skin), the GI tract, and other internal organs is decreased (centralization of blood flow by autoregulatory mechanisms). Additionally, vasoconstriction of precapillary resistance vessels raises systemic vascular resistance and reduces hydrostatic pressure in capillaries, increasing reabsorption of interstitial fluids into vessels.
Autoregulation of organ perfusion
To keep blood flow within organs constant.
- Myogenic mechanism
- Site of action: arteries and arterioles
- Mechanism of action: release of vasoactive substances
- Nitric oxide (NO): produced in endothelium by NO-synthase from arginine → vasodilation
- Other substances: kinin, histamine, serotonin, prostaglandins, thromboxane
Central regulation of organ perfusion
- Differing effects of catecholamines
Cardiac blood pressures
- Right atrium: < 5 mm Hg
- Right ventricle (pulmonary artery pressure): 25/5 mm Hg
- Left atrium (pulmonary capillary wedge pressure): < 12 mm Hg
- Left ventricle: 130/10 mm Hg
- The resistance offered by the circulatory system that must be overcome to create a blood flow.
- Factors that affect vascular resistance are determined by .
- Blood viscosity: An increase in blood viscosity leads to an increase in the vascular resistance
- Vessel length: An increase in the length of a vessel leads to an increase in vascular resistance.
- Vessel radius: An increase in the radius of a vessel leads to a decrease in vascular resistance. Vascular resistance is inversely proportional to the fourth power of the vessel radius, see pathophysiology in
- Resistances in parallel or series:
|Parallel resistance||Series resistance|
|Definition|| || |
|Characteristics|| || |
Blood flow varies greatly among tissues:
|Organs||% of cardiac output at rest||% of cardiac output during exercise|
|Viscera (hepatic-splanchnic circulation)||24||1|
Autoregulation of different organs
- Pulmonary blood flow constitutes the entire cardiac output.
- Adjustment of vascular perfusion to ventilation → hypoventilation (hypoxia) causes vasoconstriction (Euler-Liljestrand mechanism)
- Account for 1% of body weight but receive 20% of cardiac output (cleansing function)
- Low O2 extraction (∼10%)
- Regulation: mainly myogenic autoregulation
- Accounts for the greatest proportion of body mass (45%), but it receives only 21% of blood flow at rest → blood flow can be increased (20–30 times) during exercise
- Accounts for only 2% of body weight but receives 13% of cardiac output
- Very constant total blood supply
- Local blood flow depends on activities
- Regulation: local metabolic autoregulation (CO2, pH → vasodilation) and myogenic mechanism
- Level of skin blood flow is determined by how much is needed for the regulation of body temperature.
- Regulated through capillaries and arteriovenous anastomoses
- Regulation: mainly sympathetic innervation
- Highest arteriovenous O2 difference of all organs (O2 extraction at rest ∼ 60–80%)
- During exercise, there is little capacity to increase myocardial oxygen extraction (small coronary flow reserve)
- Regulation: local metabolic autoregulation (adenosine and NO increase blood flow and oxygen delivery to the heart by vasodilatation of the coronary arteries)